Journal of Pathology and Translational Medicine

Reviews

Clinical practice recommendations for the use of next-generation sequencing in patients with solid cancer: a joint report from KSMO and KSP: Miso Kim, Hyo Sup Shim, Sheehyun Kim, In Hee Lee, Jihun Kim, Shinkyo Yoon, Hyung-Don Kim, Inkeun Park, Jae Ho Jeong, Changhoon Yoo, Jaekyung Cheon, In-Ho Kim, Jieun Lee, Sook Hee Hong, Sehhoon Park, Hyun Ae Jung, Jin Won Kim, Han Jo Kim, Yongjun Cha, Sun Min Lim, Han Sang Kim, Choong-Kun Lee, Jee Hung Kim, Sang Hoon Chun, Jina Yun, So Yeon Park, Hye Seung Lee, Yong Mee Cho, Soo Jeong Nam, Kiyong Na, Sun Och Yoon, Ahwon Lee, Kee-Taek Jang, Hongseok Yun, Sungyoung Lee, Jee Hyun Kim, Wan-Seop Kim; Received September 15, 2023 Accepted November 1, 2023 Published online January 10, 2024; DOI: https://doi.org/10.4132/jptm.2023.11.01 [Epub ahead of print]

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Abstract PDF: In recent years, next-generation sequencing (NGS)–based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Perspectives on single-nucleus RNA sequencing in different cell types and tissues: Nayoung Kim, Huiram Kang, Areum Jo, Seung-Ah Yoo, Hae-Ock Lee; J Pathol Transl Med. 2023;57(1):52-59. Published online January 10, 2023; DOI: https://doi.org/10.4132/jptm.2022.12.19

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Single-cell RNA sequencing has become a powerful and essential tool for delineating cellular diversity in normal tissues and alterations in disease states. For certain cell types and conditions, there are difficulties in isolating intact cells for transcriptome profiling due to their fragility, large size, tight interconnections, and other factors. Single-nucleus RNA sequencing (snRNA-seq) is an alternative or complementary approach for cells that are difficult to isolate. In this review, we will provide an overview of the experimental and analysis steps of snRNA-seq to understand the methods and characteristics of general and tissue-specific snRNA-seq data. Knowing the advantages and limitations of snRNA-seq will increase its use and improve the biological interpretation of the data generated using this technique.

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Mapping the cellular landscape of Atlantic salmon head kidney by single cell and single nucleus transcriptomics
Adriana M.S. Andresen, Richard S. Taylor, Unni Grimholt, Rose Ruiz Daniels, Jianxuan Sun, Ross Dobie, Neil C. Henderson, Samuel A.M. Martin, Daniel J. Macqueen, Johanna H. Fosse
Fish & Shellfish Immunology.2024; 146: 109357. CrossRef
Impaired cortical neuronal homeostasis and cognition after diffuse traumatic brain injury are dependent on microglia and type I interferon responses
Jonathan M. Packer, Chelsea E. Bray, Nicolas B. Beckman, Lynde M. Wangler, Amara C. Davis, Ethan J. Goodman, Nathaniel E. Klingele, Jonathan P. Godbout
Glia.2024; 72(2): 300. CrossRef
Adipose tissue macrophage heterogeneity in the single-cell genomics era
Haneul Kang, Jongsoon Lee
Molecules and Cells.2024; 47(2): 100031. CrossRef
Single-cell and spatially resolved transcriptomics for liver biology
Ping Lin, Xi Yan, Siyu Jing, Yanhong Wu, Yiran Shan, Wenbo Guo, Jin Gu, Yu Li, Haibing Zhang, Hong Li
Hepatology.2023;[Epub] CrossRef
Integrated analysis of single-cell and bulk RNA-seq establishes a novel signature for prediction in gastric cancer
Fei Wen, Xin Guan, Hai-Xia Qu, Xiang-Jun Jiang
World Journal of Gastrointestinal Oncology.2023; 15(7): 1215. CrossRef
Placental single cell transcriptomics: Opportunities for endocrine disrupting chemical toxicology
Elana R. Elkin, Kyle A. Campbell, Samantha Lapehn, Sean M. Harris, Vasantha Padmanabhan, Kelly M. Bakulski, Alison G. Paquette
Molecular and Cellular Endocrinology.2023; 578: 112066. CrossRef
Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
Mohammad-Erfan Farhadieh, Kamran Ghaedi
Frontiers in Molecular Neuroscience.2023;[Epub] CrossRef
Single-nucleus transcriptome inventory of giant panda reveals cellular basis for fitness optimization under low metabolism
Shangchen Yang, Tianming Lan, Rongping Wei, Ling Zhang, Lin Lin, Hanyu Du, Yunting Huang, Guiquan Zhang, Shan Huang, Minhui Shi, Chengdong Wang, Qing Wang, Rengui Li, Lei Han, Dan Tang, Haimeng Li, Hemin Zhang, Jie Cui, Haorong Lu, Jinrong Huang, Yonglun
BMC Biology.2023;[Epub] CrossRef
Single-cell transcriptomics in thyroid eye disease
Sofia Ahsanuddin, Albert Y. Wu
Taiwan Journal of Ophthalmology.2023;[Epub] CrossRef

Single-cell and spatial sequencing application in pathology: Yoon-Seob Kim, Jinyong Choi, Sug Hyung Lee; J Pathol Transl Med. 2023;57(1):43-51. Published online January 10, 2023; DOI: https://doi.org/10.4132/jptm.2022.12.12

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Abstract PDF

Traditionally, diagnostic pathology uses histology representing structural alterations in a disease’s cells and tissues. In many cases, however, it is supplemented by other morphology-based methods such as immunohistochemistry and fluorescent in situ hybridization. Single-cell RNA sequencing (scRNA-seq) is one of the strategies that may help tackle the heterogeneous cells in a disease, but it does not usually provide histologic information. Spatial sequencing is designed to assign cell types, subtypes, or states according to the mRNA expression on a histological section by RNA sequencing. It can provide mRNA expressions not only of diseased cells, such as cancer cells but also of stromal cells, such as immune cells, fibroblasts, and vascular cells. In this review, we studied current methods of spatial transcriptome sequencing based on their technical backgrounds, tissue preparation, and analytic procedures. With the pathology examples, useful recommendations for pathologists who are just getting started to use spatial sequencing analysis in research are provided here. In addition, leveraging spatial sequencing by integration with scRNA-seq is reviewed. With the advantages of simultaneous histologic and single-cell information, spatial sequencing may give a molecular basis for pathological diagnosis, improve our understanding of diseases, and have potential clinical applications in prognostics and diagnostic pathology.

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Incorporating Novel Technologies in Precision Oncology for Colorectal Cancer: Advancing Personalized Medicine
Pankaj Ahluwalia, Kalyani Ballur, Tiffanie Leeman, Ashutosh Vashisht, Harmanpreet Singh, Nivin Omar, Ashis K. Mondal, Kumar Vaibhav, Babak Baban, Ravindra Kolhe
Cancers.2024; 16(3): 480. CrossRef
Potential therapeutic targets for hypotension in duchenne muscular dystrophy
Harshi Saxena, Neal L. Weintraub, Yaoliang Tang
Medical Hypotheses.2024; 185: 111318. CrossRef
A comparative analysis of single-cell transcriptomic technologies in plants and animals
Vamsidhar Reddy Netla, Harshraj Shinde, Gulshan Kumar, Ambika Dudhate, Jong Chan Hong, Ulhas Sopanrao Kadam
Current Plant Biology.2023; 35-36: 100289. CrossRef
Fibroblasts – the cellular choreographers of wound healing
Samuel Knoedler, Sonja Broichhausen, Ruiji Guo, Ruoxuan Dai, Leonard Knoedler, Martin Kauke-Navarro, Fortunay Diatta, Bohdan Pomahac, Hans-Guenther Machens, Dongsheng Jiang, Yuval Rinkevich
Frontiers in Immunology.2023;[Epub] CrossRef

Original Article

Landscape of EGFR mutations in lung adenocarcinoma: a single institute experience with comparison of PANAMutyper testing and targeted next-generation sequencing: Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung; J Pathol Transl Med. 2022;56(5):249-259. Published online September 13, 2022; DOI: https://doi.org/10.4132/jptm.2022.06.11

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Abstract PDF Supplementary Material: Background
Activating mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) are predictive biomarkers for response to EGFR–tyrosine kinase inhibitor (TKI) therapy in lung adenocarcinoma (LUAD). Here, we characterized the clinicopathologic features associated with EGFR mutations via peptide nucleic acid clamping-assisted fluorescence melting curve analysis (PANAMutyper) and evaluated the feasibility of targeted deep sequencing for detecting the mutations.
Methods
We examined EGFR mutations in exons 18 through 21 for 2,088 LUADs from July 2017 to April 2020 using PANAMutyper. Of these, we performed targeted deep sequencing in 73 patients and evaluated EGFR-mutation status and TKI clinical response.
Results
EGFR mutation was identified in 55.7% of LUADs by PANAMutyper, with mutation rates higher in females (69.3%) and never smokers (67.1%) and highest in the age range of 50 to 59 years (64.9%). For the 73 patients evaluated using both methods, next-generation sequencing (NGS) identified EGFR mutation–positive results in 14 of 61 patients (23.0%) who were EGFR-negative according to PANAMutyper testing. Of the 10 patients reportedly harboring a sensitizing mutation according to NGS, seven received TKI treatment, with all showing partial response or stable disease. In the 12 PANAMutyper-positive cases, NGS identified two additional mutations in exon 18, whereas a discordant negative result was observed in two cases.
Conclusions
Although PANAMutyper identified high frequencies of EGFR mutations, targeted deep sequencing revealed additional uncommon EGFR mutations. These findings suggested that appropriate use of NGS may benefit LUAD patients with otherwise negative screening test results.

Review

Lymphoproliferative disorder involving body fluid: diagnostic approaches and roles of ancillary studies: Jiwon Koh, Sun Ah Shin, Ji Ae Lee, Yoon Kyung Jeon; J Pathol Transl Med. 2022;56(4):173-186. Published online July 4, 2022; DOI: https://doi.org/10.4132/jptm.2022.05.16

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Abstract PDF

Lymphocyte-rich effusions represent benign reactive process or neoplastic condition. Involvement of lymphoproliferative disease in body cavity is not uncommon, and it often causes diagnostic challenge. In this review, we suggest a practical diagnostic approach toward lymphocyte-rich effusions, share representative cases, and discuss the utility of ancillary tests. Cytomorphologic features favoring neoplastic condition include high cellularity, cellular atypia/pleomorphism, monomorphic cell population, and frequent apoptosis, whereas lack of atypia, polymorphic cell population, and predominance of small T cells usually represent benign reactive process. Involvement of non-hematolymphoid malignant cells in body fluid should be ruled out first, followed by categorization of the samples into either small/medium-sized cell dominant or large-sized cell dominant fluid. Small/medium-sized cell dominant effusions require ancillary tests when either cellular atypia or history/clinical suspicion of lymphoproliferative disease is present. Large-sized cell dominant effusions usually suggest neoplastic condition, however, in the settings of initial presentation or low overall cellularity, ancillary studies are helpful for more clarification. Ancillary tests including immunocytochemistry, in situ hybridization, clonality test, and next-generation sequencing can be performed using cytologic preparations. Throughout the diagnostic process, proper review of clinical history, cytomorphologic examination, and application of adequate ancillary tests are key elements for successful diagnosis.

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The urgency of Burkitt lymphoma diagnosis in fluid cytology—A tertiary care experience
Soundarya Ravi, Anu K. Devi, Prabhu Manivannan, Debasis Gochhait, Rakhee Kar, Neelaiah Siddaraju
Cytopathology.2024; 35(2): 275. CrossRef
Immunocytochemistry on frozen-embedded cell block for the diagnosis of hematolymphoid cytology specimen: a straightforward alternative to the conventional cell block
Youjeong Seo, Sanzida Alam Prome, Lucia Kim, Jee Young Han, Joon Mee Kim, Suk Jin Choi
Journal of Hematopathology.2024; 17(1): 1. CrossRef
Lymphoma presenting as the first finding in pleural fluid cytology: A rare cytologic presentation
Kafil Akhtar, Gowthami Nagendhran, Anjum Ara, Masheera Akhtar
IP Archives of Cytology and Histopathology Research.2024; 8(4): 250. CrossRef

Case Studies

Adrenal hemangioblastoma: Joo-Yeon Koo, Kyung-Hwa Lee, Joon Hyuk Choi, Ho Seok Chung, Chan Choi; J Pathol Transl Med. 2022;56(3):161-166. Published online February 28, 2022; DOI: https://doi.org/10.4132/jptm.2021.12.28

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Abstract PDF: Hemangioblastoma (HB) is a rare benign tumor that most commonly occurs in the cerebellum. HB is composed of neoplastic stromal cells and abundant small vessels. However, the exact origin of stromal cells is controversial. Extraneural HBs have been reported in a small series, and peripheral HBs arising in the adrenal gland are extremely rare. Herein, we report a case of sporadic adrenal HB in a 54-year-old woman. The tumor was a well-circumscribed, yellow mass measuring 4.2 cm in diameter. Histologically, the tumor was composed of small blood vessels and vacuolated stromal cells with clear cytoplasm. On immunohistochemical stain, the stromal cells were positive for S-100 protein, neuron-specific enolase, and synaptophysin. The tumor did not reveal mutation of VHL alleles. We herein present a case of HB of the adrenal gland and review of the literature.

An unusual case of microsatellite instability–high/deficient mismatch repair (MSI-H/dMMR) diffuse large B-cell lymphoma revealed by targeted gene sequencing: Bogyeong Han, Sehui Kim, Jiwon Koh, Jeong Mo Bae, Hongseok Yun, Yoon Kyung Jeon; J Pathol Transl Med. 2022;56(2):92-96. Published online November 16, 2021; DOI: https://doi.org/10.4132/jptm.2021.10.15

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Abstract PDF

Microsatellite instability-high/deficient mismatch repair (MSI-H/dMMR) status has been approved as a tissue-agnostic biomarker for immune checkpoint inhibitor therapy in patients with solid tumors. We report the case of an MSI-H/dMMR diffuse large B-cell lymphoma (DLBCL) identified by targeted gene sequencing (TGS). A 90-year-old female who presented with vaginal bleeding and a large mass in the upper vagina was diagnosed with germinal center-B-cell-like DLBCL, which recurred at the uterine cervix at 9 months after chemotherapy. Based on TGS of 121 lymphoma-related genes and the LymphGen algorithm, the tumor was classified genetically as DLBCL of EZB subtype. Mutations in multiple genes, including frequent frameshift mutations, were detected by TGS and further suggested MSI. The MSI-H/dMMR and loss of MLH1 and PMS2 expression were determined in MSI-fragment analysis, MSI real-time polymerase chain reaction, and immunohistochemical tests. This case demonstrates the potential diagnostic and therapeutic utility of lymphoma panel sequencing for DLBCL with MSI-H/dMMR.

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Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family
Jens Staal, Yasmine Driege, Femke Van Gaever, Jill Steels, Rudi Beyaert
The FEBS Journal.2024; 291(6): 1220. CrossRef
PD-L1+diffuse large B-cell lymphoma with extremely high mutational burden and microsatellite instability due to acquiredPMS2mutation
Andrew W. Allbee, James Gerson, Guang Yang, Adam Bagg
Molecular Case Studies.2023; 9(4): a006318. CrossRef

Original Article

A study of pathological characteristics and BRAF V600E status in Langerhans cell histiocytosis of Vietnamese children: Thu Dang Anh Phan, Bao Gia Phung, Tu Thanh Duong, Vu Anh Hoang, Dat Quoc Ngo, Nguyen Dinh The Trinh, Tung Thanh Tran; J Pathol Transl Med. 2021;55(2):112-117. Published online January 27, 2021; DOI: https://doi.org/10.4132/jptm.2020.11.30

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Abstract PDF

Background
Langerhans cell histiocytosis (LCH) is more common in children than adults and involves many organs. In children, the BRAF V600E mutation is associated with recurrent and high-risk LCH.
Methods
We collected paraffin blocks of 94 pediatric LCH patients to detect BRAF V600E mutation by sequencing. The relationship between BRAF V600E status and clinicopathological parameters were also critically analyzed.
Results
BRAF V600E mutation exon 15 was detected in 45 cases (47.9%). Multiple systems LCH showed a significantly higher BRAF V600E mutation rate than a single system (p=.001). No statistical significance was evident for other clinical characteristics such as age, sex, location, risk organs involvement, and CD1a expression.
Conclusions
In Vietnamese LCH children, the proportion of BRAF V600E mutational status was relatively high and related to multiple systems.

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Sulfur dots/Au@Ag nanorods array-based polarized ECL sensor for the detection of thyroid cancer biomarker
Zixuan Ding, Peilin Wang, Zhenrun Li, Yupeng Guo, Qiang Ma
Talanta.2023; 265: 124925. CrossRef

Case Study

A case of concomitant EGFR/ALK alteration against a mutated EGFR background in early-stage lung adenocarcinoma: Ki-Chang Lee, Jiwon Koh, Doo Hyun Chung, Yoon Kyung Jeon; J Pathol Transl Med. 2021;55(2):139-144. Published online January 22, 2021; DOI: https://doi.org/10.4132/jptm.2020.12.16

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Abstract PDF

Rare cases of lung adenocarcinoma (LUAD) with concomitant epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) translocation have been reported. However, their clonal and evolutional relationship remains unclear. We report a case of early-stage EGFR-mutated LUAD with a focal concomitant EGFR/ALK alteration. A 63-year-old male underwent lobectomy to remove a 1.9-cm-sized lung nodule, which was diagnosed with EGFR-mutated LUAD. ALK immunohistochemistry (IHC) showed focal positivity within the part of the tumor characterized by lepidic pattern, also confirmed by fluorescence in-situ hybridization (FISH). Targeted next-generation sequencing was performed separately on the ALK IHC/FISH-positive and -negative areas. EGFR L833V/L858R mutations were detected in both areas, whereas EML4 (echinoderm microtubule-associated protein-like 4)-ALK translocations was confirmed only in the ALK IHC/FISH-positive area, suggesting the divergence of an EGFR/ALK co-altered subclone from the original EGFR-mutant clone. Our study suggests that concurrent alterations of EGFR and ALK can arise via divergent tumor evolution, even in the relatively early phases of tumorigenesis.

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Identification and validation of molecular subtype and prognostic signature for lung adenocarcinoma based on neutrophil extracellular traps
Yanhua Zuo, Guangyi Leng, Ping Leng
Pathology and Oncology Research.2023;[Epub] CrossRef
Machine Learning-Based Integration Develops a Macrophage-Related Index for Predicting Prognosis and Immunotherapy Response in Lung Adenocarcinoma
Zuwei Li, Minzhang Guo, Wanli Lin, Peiyuan Huang
Archives of Medical Research.2023; 54(7): 102897. CrossRef
Big data analysis identified a telomere-related signature predicting the prognosis and drug sensitivity in lung adenocarcinoma
Weiyi Zhang
Medicine.2023; 102(46): e35526. CrossRef

Review

DNA-protein biomarkers for immunotherapy in the era of precision oncology: Binnari Kim, So Young Kang, Kyoung-Mee Kim; J Pathol Transl Med. 2021;55(1):26-32. Published online November 9, 2020; DOI: https://doi.org/10.4132/jptm.2020.09.23

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Abstract PDF

The use of biomarkers to guide patient and therapy selection has gained much attention to increase the scope and complexity of targeted therapy options and immunotherapy. Clinical trials provide a basis for discovery of biomarkers, which can then aid in development of new drugs. To that end, samples from cancer patients, including DNA, RNA, protein, and the metabolome isolated from cancer tissues and blood or urine, are analyzed in various ways to identify relevant biomarkers. In conjunction with nucleotide-based, high-throughput, next-generation sequencing techniques, therapy-guided biomarker assays relying on protein-based immunohistochemistry play a pivotal role in cancer care. In this review, we discuss the current knowledge regarding DNA and protein biomarkers for cancer immunotherapy

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Biomarkers for Predicting Response to Personalized Immunotherapy in Gastric Cancer
Moonsik Kim, Ji Yun Jeong, An Na Seo
Diagnostics.2023; 13(17): 2782. CrossRef

Original Article

Prediction of TP53 mutations by p53 immunohistochemistry and their prognostic significance in gastric cancer: Hye Jung Hwang, Soo Kyung Nam, Hyunjin Park, Yujun Park, Jiwon Koh, Hee Young Na, Yoonjin Kwak, Woo Ho Kim, Hye Seung Lee; J Pathol Transl Med. 2020;54(5):378-386. Published online July 1, 2020; DOI: https://doi.org/10.4132/jptm.2020.06.01

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Abstract PDF Supplementary Material

Background
Recently, molecular classifications of gastric cancer (GC) have been proposed that include TP53 mutations and their functional activity. We aimed to demonstrate the correlation between p53 immunohistochemistry (IHC) and TP53 mutations as well as their clinicopathological significance in GC.
Methods
Deep targeted sequencing was performed using surgical or biopsy specimens from 120 patients with GC. IHC for p53 was performed and interpreted as strong, weak, or negative expression. In 18 cases (15.0%) with discrepant TP53 mutation and p53 IHC results, p53 IHC was repeated.
Results
Strong expression of p53 was associated with TP53 missense mutations, negative expression with other types of mutations, and weak expression with wild-type TP53 (p<.001). The sensitivity for each category was 90.9%, 79.0%, and 80.9%, and the specificity was 95.4%, 88.1%, and 92.3%, respectively. The TNM stage at initial diagnosis exhibited a significant correlation with both TP53 mutation type (p=.004) and p53 expression status (p=.029). The Kaplan-Meier survival analysis for 109 stage II and III GC cases showed that patients with TP53 missense mutations had worse overall survival than those in the wild-type and other mutation groups (p=.028). Strong expression of p53 was also associated with worse overall survival in comparison to negative and weak expression (p=.035).
Conclusions
Results of IHC of the p53 protein may be used as a simple surrogate marker of TP53 mutations. However, negative expression of p53 and other types of mutations of TP53 should be carefully interpreted because of its lower sensitivity and different prognostic implications.

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Multiple approaches revealed MGc80‐3 as a somatic hybrid with HeLa cells rather than a gastric cancer cell line
Fang Cao, Hao Sun, Zhenli Yang, Yanhua Bai, Xiao Hu, Yuhong Hou, Xiaocui Bian, Yuqin Liu
International Journal of Cancer.2024; 154(1): 155. CrossRef
In Response to p53 Immunohistochemical Staining and TP53 Gene Mutations in Endometrial Cancer: Does Null Pattern Correlate With Prognosis?
Ikuko Sakamoto, Keiko Kagami, Takahiro Nozaki, Yosuke Hirotsu, Kenji Amemiya, Toshio Oyama, Masao Omata
American Journal of Surgical Pathology.2024; 48(3): 374. CrossRef
CHEK2 germline variants identified in familial nonmedullary thyroid cancer lead to impaired protein structure and function
Carolina Pires, Inês J. Marques, Mariana Valério, Ana Saramago, Paulo E. Santo, Sandra Santos, Margarida Silva, Margarida M. Moura, João Matos, Teresa Pereira, Rafael Cabrera, Diana Lousa, Valeriano Leite, Tiago M. Bandeiras, João B. Vicente, Branca M. Ca
Journal of Biological Chemistry.2024; 300(3): 105767. CrossRef
The spectrum of TP53 mutations in Rwandan patients with gastric cancer
Augustin Nzitakera, Jean Bosco Surwumwe, Ella Larissa Ndoricyimpaye, Schifra Uwamungu, Delphine Uwamariya, Felix Manirakiza, Marie Claire Ndayisaba, Gervais Ntakirutimana, Benoit Seminega, Vincent Dusabejambo, Eric Rutaganda, Placide Kamali, François Ngab
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Application of NGS molecular classification in the diagnosis of endometrial carcinoma: A supplement to traditional pathological diagnosis
Qunxian Rao, Jianwei Liao, Yangyang Li, Xin Zhang, Guocai Xu, Changbin Zhu, Shengya Tian, Qiuhong Chen, Hui Zhou, Bingzhong Zhang
Cancer Medicine.2023; 12(5): 5409. CrossRef
Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer
Kenji Morimoto, Tadaaki Yamada, Ryo Sawada, Koichi Azuma, Yasuhiro Goto, Taishi Harada, Shinsuke Shiotsu, Nobuyo Tamiya, Yusuke Chihara, Takayuki Takeda, Osamu Hiranuma, Isao Hasegawa, Satomi Tanaka, Akihiro Yoshimura, Masahiro Iwasaku, Shinsaku Tokuda, Y
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Validation of p53 Immunohistochemistry (PAb240 Clone) in Canine Tumors with Next-Generation Sequencing (NGS) Analysis
Barbara Brunetti, Dario de Biase, Giulia Dellapina, Luisa Vera Muscatello, Francesco Ingravalle, Giorgia Tura, Barbara Bacci
Animals.2023; 13(5): 899. CrossRef
Mesonephric‐like adenocarcinoma of the female genital tract: novel observations and detailed molecular characterisation of mixed tumours and mesonephric‐like carcinosarcomas
Jelena Mirkovic, Ekaterina Olkhov‐Mitsel, Yutaka Amemiya, Maysa Al‐Hussaini, Sharon Nofech‐Mozes, Bojana Djordjevic, Rachel Kupets, Arun Seth, W Glenn McCluggage
Histopathology.2023; 82(7): 978. CrossRef
Clinicopathologic characterization of cervical metastasis from an unknown primary tumor: a multicenter study in Korea
Miseon Lee, Uiree Jo, Joon Seon Song, Youn Soo Lee, Chang Gok Woo, Dong-Hoon Kim, Jung Yeon Kim, Sun Och Yoon, Kyung-Ja Cho
Journal of Pathology and Translational Medicine.2023; 57(3): 166. CrossRef
P53 in Penile Squamous Cell Carcinoma: A Pattern-Based Immunohistochemical Framework with Molecular Correlation
Isabel Trias, Adela Saco, Lorena Marimon, Ricardo López del Campo, Carolina Manzotti, Oriol Ordi, Marta del Pino, Francisco M. Pérez, Naiara Vega, Silvia Alós, Antonio Martínez, Leonardo Rodriguez-Carunchio, Oscar Reig, Pedro Jares, Cristina Teixido, Tare
Cancers.2023; 15(10): 2719. CrossRef
p53/TP53 Status Assessment in Gastroesophageal Adenocarcinoma
Elisa Boldrin, Maria Assunta Piano, Francesco Bernaudo, Rita Alfieri, Maria Raffaella Biasin, Isabella Monia Montagner, Alice Volpato, Genny Mattara, Francesco Lamacchia, Giovanna Magni, Antonio Rosato, Antonio Scapinello, Pierluigi Pilati, Matteo Curtare
Cancers.2023; 15(10): 2783. CrossRef
Genomic profiling of dedifferentiated endometrial carcinomas arising in the background of high‐grade carcinoma: a targeted next‐generation sequencing study
Ekaterina Olkhov‐Mitsel, Aurelia Busca, Carlos Parra‐Herran, Yutaka Amemiya, Sharon Nofech‐Mozes, Bojana Djordjevic, Marisa R Nucci, Arun Seth, Jelena Mirkovic
Histopathology.2023; 83(3): 366. CrossRef
Clinicopathologic Features and Prognostic Significance of Immunohistochemistry and In Situ Hybridization Based Molecular Classification in Gastric Carcinoma
Gizem Issin, İlyas Sayar, Fatih Demir, İrem Güvendir Bakkaloğlu, Mehmet Gamsizkan, Zeliha Yildiz, Ismail Yilmaz, Sevilay Akalp Özmen, Diren Vuslat Çağatay, Itır Ebru Zemheri, Murat Demiriz, Armağan Günal
Journal of Environmental Pathology, Toxicology and Oncology.2023; 42(4): 1. CrossRef
Clinicopathologic and Molecular Characterization of Anorectal Neuroendocrine Carcinomas Reveals Human Papillomavirus, p53, and c-Myc as Alternative Mechanisms of Carcinogenesis
Allison J. Cox, William E. Crowe, Qi Yang, Bin Zhang, Zoltán N. Oltvai, Xiaoyan Liao
Modern Pathology.2023; 36(11): 100295. CrossRef
Dedifferentiated Endometrial Carcinoma: A Rare Aggressive Neoplasm-Clinical, Morphological and Immunohistochemical Features
Giovanna Giordano, Elena Ferioli, Debora Guareschi, Alessandro Tafuni
Cancers.2023; 15(21): 5155. CrossRef
Characterization on the oncogenic effect of the missense mutations of p53 via machine learning
Qisheng Pan, Stephanie Portelli, Thanh Binh Nguyen, David B Ascher
Briefings in Bioinformatics.2023;[Epub] CrossRef
Adrenal Nodules Detected at Staging CT in Patients with Resectable Gastric Cancers Have a Low Incidence of Malignancy
Hae Young Kim, Won Chang, Yoon Jin Lee, Ji Hoon Park, Jungheum Cho, Hee Young Na, Hyungwoo Ahn, Sung Il Hwang, Hak Jong Lee, Young Hoon Kim, Kyoung Ho Lee
Radiology.2022; 302(1): 129. CrossRef
Intestinal-type gastric dysplasia in Helicobacter pylori-naïve patients
Kotaro Shibagaki, Ayako Itawaki, Yoichi Miyaoka, Kenichi Kishimoto, Yusuke Takahashi, Satoshi Kotani, Tsuyoshi Mishiro, Naoki Oshima, Kousaku Kawashima, Norihisa Ishimura, Hideyuki Onuma, Makoto Nagasaki, Mamiko Nagase, Asuka Araki, Kyuichi Kadota, Ryoji
Virchows Archiv.2022; 480(4): 783. CrossRef
Dedifferentiation-like tubular and solid carcinoma of the stomach shows phenotypic divergence and association with deficient SWI/SNF complex
Shih-Chiang Huang, Kuang-Hua Chen, Kwai-Fong Ng, I-Chieh Lin, Yi-Chun Chao, Ta-Sen Yeh, Huei-Chieh Chuang, Tse-Ching Chen
Virchows Archiv.2022; 480(4): 771. CrossRef
Distinct molecular phenotype and the potential prognostic value of immune prognostic index and tumor infiltrating lymphocytes in hepatoid adenocarcinoma of stomach
Muxing Kang, Xiaojing Ma, Jifei Shi, Guofeng Chen, Xiaoli Jin, Jun Wang, Lele Lin, Zhiwei Wu, Kaibo Chen, Jinghong Xu, Pintong Huang, Jian Chen
Translational Oncology.2022; 19: 101380. CrossRef
Evaluation of Tumor DNA Sequencing Results in Patients with Gastric and Gastroesophageal Junction Adenocarcinoma Stratified by TP53 Mutation Status
Anthony C Wood, Yonghong Zhang, Qianxing Mo, Ling Cen, Jacques Fontaine, Sarah E Hoffe, Jessica Frakes, Sean P Dineen, Jose M Pimiento, Christine M Walko, Rutika Mehta
The Oncologist.2022; 27(4): 307. CrossRef
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Yangyang Wang, Bingfeng Huang, Qihan Fu, Jianing Wang, Mao Ye, Manyi Hu, Kai Qu, Kai Liu, Xiao Hu, Shumei Wei, Ke Sun, Wenbo Xiao, Bo Zhang, Haijun Li, Jingsong Li, Qi Zhang, Tingbo Liang
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Li Liang, Yijie Chai, Fei Chai, Haijing Liu, Ningning Ma, Hong Zhang, Shuang Zhang, Lin Nong, Ting Li, Bo Zhang
Pathology and Oncology Research.2022;[Epub] CrossRef
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Iasmin Moreira Costa Bispo, Henry Paul Granger, Palloma Porto Almeida, Patricia Belini Nishiyama, Leandro Martins de Freitas
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Joon Im, Soo Kyung Nam, Hye Seung Lee
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Case Study

Morule-like features in pulmonary adenocarcinoma associated with epidermal growth factor receptor mutations: two case reports with targeted next-generation sequencing analysis: Yoo Jin Lee, Harim Oh, Eojin Kim, Bokyung Ahn, Jeong Hyeon Lee, Youngseok Lee, Yang Seok Chae, Chul Hwan Kim; J Pathol Transl Med. 2020;54(1):119-122. Published online November 1, 2019; DOI: https://doi.org/10.4132/jptm.2019.09.30

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120 Download
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Abstract PDF

Morules, or morule-like features, can be identified in benign and malignant lesions in various organs. Morular features are unusual in pulmonary adenocarcinoma cases with only 26 cases reported to date. Here, we describe two cases of pulmonary adenocarcinoma with morule-like features in Korean women. One patient had a non-mucinous-type adenocarcinoma in situ and the other had an acinarpredominant adenocarcinoma with a micropapillary component. Both patients showed multiple intra-alveolar, nodular, whorled proliferative foci composed of atypical spindle cells with eosinophilic cytoplasm. Targeted next-generation sequencing was performed on DNA extracted from formalin-fixed paraffin-embedded samples of the tumors. Results showed unusual epidermal growth factor receptor (EGFR) mutations, which are associated with drug resistance to EGFR tyrosine kinase inhibitors, revealing the importance of identifying morule-like features in pulmonary adenocarcinoma and the need for additional study, since there are few reported cases.

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Pulmonary adenocarcinoma in situ with morule - like components: A surgical case report
Mitsuteru Yosida, Mitsuru Tomita, Naoya Kawakita, Teruki Shimizu, Ryou Yamada, Hiromitsu Takizawa, Hisanori Uehara
Respiratory Medicine Case Reports.2024; 48: 102008. CrossRef
Clinicopathological, Radiological, and Molecular Features of Primary Lung Adenocarcinoma with Morule-Like Components
Li-Li Wang, Li Ding, Peng Zhao, Jing-Jing Guan, Xiao-Bin Ji, Xiao-Li Zhou, Shi-Hong Shao, Yu-Wei Zou, Wei-Wei Fu, Dong-Liang Lin, Dong Pan
Disease Markers.2021; 2021: 1. CrossRef

Original Articles

Utility of BRAF VE1 Immunohistochemistry as a Screening Tool for Colorectal Cancer Harboring BRAF V600E Mutation: Jeong-Hwa Kwon, Byung-Kwan Jeong, Yong Sik Yoon, Chang Sik Yu, Jihun Kim; J Pathol Transl Med. 2018;52(3):157-163. Published online March 29, 2018; DOI: https://doi.org/10.4132/jptm.2018.03.28

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166 Download
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Abstract PDF Supplementary Material

Background
BRAF mutation has been recognized as an important biomarker of colorectal cancer (CRC) for targeted therapy and prognosis prediction. However, sequencing for every CRC case is not cost-effective. An antibody specific for BRAF V600E mutant protein has been introduced, and we thus examined the utility of BRAF VE1 immunohistochemistry for evaluating BRAF mutations in CRC.
Methods
Fifty-one BRAF-mutated CRCs and 100 age and sexmatched BRAF wild-type CRCs between 2005 and 2015 were selected from the archives of Asan Medical Center. Tissue microarrays were constructed and stained with BRAF VE1 antibody.
Results
Forty-nine of the 51 BRAF-mutant CRCs (96.1%) showed more than moderate cytoplasmic staining, except for two weakly stained cases. Six of 100 BRAF wild-type cases also stained positive with BRAF VE1 antibody; four stained weakly and two stained moderately. Normal colonic crypts showed nonspecific weak staining, and a few CRC cases exhibited moderate nuclear reactivity (3 BRAF-mutant and 10 BRAF wild-type cases). BRAF-mutated CRC patients had higher pathologic stages and worse survival than BRAF wild-type patients.
Conclusions
BRAF VE1 immunohistochemistry showed high sensitivity and specificity, but occasional nonspecific staining in tumor cell nuclei and normal colonic crypts may limit their routine clinical use. Thus, BRAF VE1 immunohistochemistry may be a useful screening tool for BRAF V600E mutation in CRCs, provided that additional sequencing studies can be done to confirm the mutation in BRAF VE1 antibody-positive cases.

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Immunohistochemistry as a Surrogate Marker of Underlying Molecular Derangements in Sporadic Colorectal Carcinoma in Children – A Series of Three Cases
Priyanka Maity, Aniket Halder, Ranajoy Ghosh, Uttara Chatterjee, Shibsankar Barman, Ruchirendra Sarkar
Fetal and Pediatric Pathology.2022; 41(1): 98. CrossRef
Risk assessment and genetic counseling for Lynch syndrome – Practice resource of the National Society of Genetic Counselors and the Collaborative Group of the Americas on Inherited Gastrointestinal Cancer
Spring Holter, Michael J. Hall, Heather Hampel, Kory Jasperson, Sonia S. Kupfer, Joy Larsen Haidle, Maureen E. Mork, Selvi Palaniapppan, Leigha Senter, Elena M. Stoffel, Scott M. Weissman, Matthew B. Yurgelun
Journal of Genetic Counseling.2022; 31(3): 568. CrossRef
Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review
Rogelio González-González, Sandra López-Verdín, Jesús Lavalle-Carrasco, Nelly Molina-Frechero, Mario Isiordia-Espinoza, Ramón G Carreón-Burciaga, Ronell Bologna-Molina
World Journal of Clinical Oncology.2020; 11(1): 31. CrossRef
Genetic and histopathological analysis of a case of primary intraosseous carcinoma, NOS with features of both ameloblastic carcinoma and squamous cell carcinoma
Akane Yukimori, Maiko Tsuchiya, Akane Wada, Yasuyuki Michi, Kou Kayamori, Kei Sakamoto, Tohru Ikeda
World Journal of Surgical Oncology.2020;[Epub] CrossRef

Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01): Bo Mi Ku, Mi Hwa Heo, Joo-Hang Kim, Byoung Chul Cho, Eun Kyung Cho, Young Joo Min, Ki Hyeong Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Tae Jung Kim, Ho Yun Lee, Hojoong Kim, Kyung-Jong Lee, Myung-Ju Ahn; J Pathol Transl Med. 2018;52(3):148-156. Published online March 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.03.12

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295 Download
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Abstract PDF

Background
Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC.
Methods
DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Results
The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study.
Conclusions
These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

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Jeonghyo Lee, Yeon Bi Han, Hyun Jung Kwon, Song Kook Lee, Hyojin Kim, Jin-Haeng Chung
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Quincy S. Chu
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Hersh A. Ham-Karim, Henry Okuchukwu Ebili, Kirsty Manger, Wakkas Fadhil, Narmeen S. Ahmad, Susan D. Richman, Mohammad Ilyas
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Small lung tumor biopsy samples are feasible for high quality targeted next generation sequencing
Hidenori Kage, Shinji Kohsaka, Aya Shinozaki‐Ushiku, Yoshihisa Hiraishi, Jiro Sato, Kazuhiro Nagayama, Tetsuo Ushiku, Daiya Takai, Jun Nakajima, Kiyoshi Miyagawa, Hiroyuki Aburatani, Hiroyuki Mano, Takahide Nagase
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PTEN in Lung Cancer: Dealing with the Problem, Building on New Knowledge and Turning the Game Around
Anastasios Gkountakos, Giulia Sartori, Italia Falcone, Geny Piro, Ludovica Ciuffreda, Carmine Carbone, Giampaolo Tortora, Aldo Scarpa, Emilio Bria, Michele Milella, Rafael Rosell, Vincenzo Corbo, Sara Pilotto
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Review

Molecular Testing of Brain Tumor: Sung-Hye Park, Jaekyung Won, Seong-Ik Kim, Yujin Lee, Chul-Kee Park, Seung-Ki Kim, Seung-Hong Choi; J Pathol Transl Med. 2017;51(3):205-223. Published online May 12, 2017; DOI: https://doi.org/10.4132/jptm.2017.03.08

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Abstract PDF

The World Health Organization (WHO) classification of central nervous system (CNS) tumors was revised in 2016 with a basis on the integrated diagnosis of molecular genetics. We herein provide the guidelines for using molecular genetic tests in routine pathological practice for an accurate diagnosis and appropriate management. While astrocytomas and IDH-mutant (secondary) glioblastomas are characterized by the mutational status of IDH, TP53, and ATRX, oligodendrogliomas have a 1p/19q codeletion and mutations in IDH, CIC, FUBP1, and the promoter region of telomerase reverse transcriptase (TERTp). IDH-wildtype (primary) glioblastomas typically lack mutations in IDH, but are characterized by copy number variations of EGFR, PTEN, CDKN2A/B, PDGFRA, and NF1 as well as mutations of TERTp. High-grade pediatric gliomas differ from those of adult gliomas, consisting of mutations in H3F3A, ATRX, and DAXX, but not in IDH genes. In contrast, well-circumscribed low-grade neuroepithelial tumors in children, such as pilocytic astrocytoma, pleomorphic xanthoastrocytoma, and ganglioglioma, often have mutations or activating rearrangements in the BRAF, FGFR1, and MYB genes. Other CNS tumors, such as ependymomas, neuronal and glioneuronal tumors, embryonal tumors, meningothelial, and other mesenchymal tumors have important genetic alterations, many of which are diagnostic, prognostic, and predictive markers and therapeutic targets. Therefore, the neuropathological evaluation of brain tumors is increasingly dependent on molecular genetic tests for proper classification, prediction of biological behavior and patient management. Identifying these gene abnormalities requires cost-effective and high-throughput testing, such as next-generation sequencing. Overall, this paper reviews the global guidelines and diagnostic algorithms for molecular genetic testing of brain tumors.

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